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Gerry R Boss - One of the best experts on this subject based on the ideXlab platform.

  • Intramuscular Aminotetrazole Cobinamide as a Treatment for Inhaled Hydrogen Sulfide Poisoning in a Large Swine Model
    Annals of the New York Academy of Sciences, 2020
    Co-Authors: Tara B. Hendry-hofer, Sari B. Mahon, Matthew Brenner, Alison M. Mcgrath, David Mukai, Joseph K. Maddry, Gerry R Boss, Vikhyat S. Bebarta
    Abstract:

    Hydrogen sulfide (H2 S), a high-threat chemical agent, occurs naturally in a variety of settings. Despite multiple incidents of exposures and deaths, no FDA-approved antidote exists. A rapid-acting, easy to administer antidote is needed. We conducted a randomized control trial in swine comparing intramuscular administration of aminotetrazole Cobinamide (2.9 mL, 18 mg/kg) to no treatment following inhalation of H2 S gas. We found that aminotetrazole Cobinamide administered 2 min after the onset of respiratory depression-defined as a tidal volume of less than 3 mL/kg for 2 consecutive minutes-yielded 100% survival, while all control animals died. Respiratory depression resolved in the treatment group within 3.6 ± 1.5 min (mean ± SD) of Cobinamide administration, whereas control animals had intermittent gasping until death. Blood pressure and arterial oxygen saturation (SO2 ) returned to baseline values within 5 and 10 min, respectively, of Cobinamide treatment, and plasma lactate concentration decreased to less than 50% of the highest value by the end of the experiment. In control animals, plasma lactate rose continuously until death. We conclude that intramuscular aminotetrazole Cobinamide is effective in a large animal, inhalational model of acute, severe H2 S poisoning.

  • efficacy of intravenous Cobinamide versus hydroxocobalamin or saline for treatment of severe hydrogen sulfide toxicity in a swine sus scrofa model
    Academic Emergency Medicine, 2017
    Co-Authors: Vikhyat S. Bebarta, Sari B. Mahon, Matthew Brenner, Joseph K. Maddry, Susan M Boudreau, Maria G Castaneda, Normalynn Garrett, Gerry R Boss
    Abstract:

    Background Hydrogen sulfide (H2S) is a potentially deadly gas that naturally occurs in petroleum and natural gas. The Occupational Health and Safety Administration cites H2S as a leading cause of workplace gas inhalation deaths. Mass casualties of H2S toxicity may be caused by exposure from industrial accidents or release from oil field sites. H2S is also an attractive terrorism tool because of its high toxicity and ease with which it can be produced. Several potential antidotes have been proposed for hydrogen sulfide poisoning but none have been completely successful. Objective To compare treatment response assessed by the time to spontaneous ventilation among groups of swine with acute H2S induced apnea treated with intravenous (IV) Cobinamide (4mg/kg in 0.8 ml of 225mM solution), IV hydroxocobalamin (4mg/kg in 5 ml saline), or saline alone. Methods Twenty-four swine (45-55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. After stabilization, anesthesia was adjusted such that animals would spontaneous ventilate with an FIO2 of 0.21. Sodium hydrosulfide (NaHS; concentration of 8 mg/ml) was begun at 1 mg/kg/min until apnea was confirmed for 20 seconds by capnography. This infusion rate was sustained for 1.5 minutes post apnea, and then decreased to a maintenance rate for the remainder of the study to replicate sustained clinical exposure. Animals were randomly assigned to receive Cobinamide (4 mg/kg), hydroxocobalamin (4 mg/kg) or saline and monitored for 60 minutes beginning one-minute post apnea. G* power analysis using the Z test determined that equal group sizes of 8 animals were needed to achieve a power of 80% in detecting a 50% difference in return to spontaneous ventilations at α=0.05. Results There were no significant differences in baseline variables. Moreover, there were no significant differences in the mg/kg dose of NaHS (5.6 mg/kg; p=0.45) required to produce apnea. Whereas all of the Cobinamide treated animals survived (8/8), none of the control (0/8) or hydroxocobalamin (0/8) treated animals survived. Mean time to spontaneous ventilation in the Cobinamide treated animals was 3.2(±1.1) minutes. Conclusions Cobinamide successfully rescued the severely NaHS-poisoned swine from apnea in the absence of assisted ventilation. This article is protected by copyright. All rights reserved.

  • The Vitamin B_12 Analog Cobinamide Is an Effective Antidote for Oral Cyanide Poisoning
    Journal of Medical Toxicology, 2016
    Co-Authors: Jangwoen Lee, Adriano Chan, Sari B. Mahon, David Mukai, Vikhyat S. Bebarta, Gerry R Boss, Tanya Burney, Behdod S Katebian, David Yoon, Matthew Brenner
    Abstract:

    Introduction Cyanide is a major chemical threat, and cyanide ingestion carries a higher risk for a supra-lethal dose exposure compared to inhalation but provides an opportunity for effective treatment due to a longer treatment window and a gastrointestinal cyanide reservoir that could be neutralized prior to systemic absorption. We hypothesized that orally administered Cobinamide may function as a high-binding affinity scavenger and that gastric alkalinization would reduce cyanide absorption and concurrently increase Cobinamide binding, further enhancing antidote effectiveness. Methods Thirty New Zealand white rabbits were divided into five groups and were given a lethal dose of oral cyanide poisoning (50 mg). The survival time of animals was monitored with oral cyanide alone, oral cyanide with gastric alkalinization with oral sodium bicarbonate buffer (500 mg), and in combination with either aquohydroxoCobinamide or dinitroCobinamide (250 mM). Red blood cell cyanide concentration, plasma Cobinamide, and thiocyanate concentrations were measured from blood samples. Results In cyanide ingested animals, oral sodium bicarbonate alone significantly prolonged survival time to 20.3 ± 8.6 min compared to 10.5 ± 4.3 min in saline-treated controls, but did not lead to overall survival. AquohydroxoCobinamide and dinitroCobinamide increased survival time to 64 ± 41 ( p  

  • the vitamin b12 analog Cobinamide is an effective antidote for oral cyanide poisoning
    Journal of Medical Toxicology, 2016
    Co-Authors: Jangwoen Lee, Adriano Chan, Sari B. Mahon, David Mukai, Vikhyat S. Bebarta, Gerry R Boss, Tanya Burney, Behdod S Katebian, David Yoon, Matthew Brenner
    Abstract:

    Introduction Cyanide is a major chemical threat, and cyanide ingestion carries a higher risk for a supra-lethal dose exposure compared to inhalation but provides an opportunity for effective treatment due to a longer treatment window and a gastrointestinal cyanide reservoir that could be neutralized prior to systemic absorption. We hypothesized that orally administered Cobinamide may function as a high-binding affinity scavenger and that gastric alkalinization would reduce cyanide absorption and concurrently increase Cobinamide binding, further enhancing antidote effectiveness.

  • intravenous Cobinamide versus hydroxocobalamin for acute treatment of severe cyanide poisoning in a swine sus scrofa model
    Annals of Emergency Medicine, 2014
    Co-Authors: Vikhyat S. Bebarta, Susan M Boudreau, Maria G Castaneda, David A Tanen, Lee A Zarzabal, Toni E Vargas, Gerry R Boss
    Abstract:

    Study objective Hydroxocobalamin is a Food and Drug Administration–approved antidote for cyanide poisoning. Cobinamide is a potential antidote that contains 2 cyanide-binding sites. To our knowledge, no study has directly compared hydroxocobalamin with Cobinamide in a severe, cyanide-toxic large-animal model. Our objective is to compare the time to return of spontaneous breathing in swine with acute cyanide-induced apnea treated with intravenous hydroxocobalamin, intravenous Cobinamide, or saline solution (control). Methods Thirty-three swine (45 to 55 kg) were intubated, anesthetized, and instrumented (continuous mean arterial pressure and cardiac output monitoring). Anesthesia was adjusted to allow spontaneous breathing with FiO 2 of 21% during the experiment. Cyanide was continuously infused intravenously until apnea occurred and lasted for 1 minute (time zero). Animals were then randomly assigned to receive intravenous hydroxocobalamin (65 mg/kg), Cobinamide (12.5 mg/kg), or saline solution and monitored for 60 minutes. A sample size of 11 animals per group was selected according to obtaining a power of 80%, an α of .05, and an SD of 0.17 in mean time to detect a 20% difference in time to spontaneous breathing. We assessed differences in time to death among groups, using Kaplan-Meier estimation methods, and compared serum lactate, blood pH, cardiac output, mean arterial pressure, respiratory rate, and minute ventilation time curves with repeated-measures ANOVA. Results Baseline weights and vital signs were similar among groups. The time to apnea and cyanide dose required to achieve apnea were similar. At time zero, mean cyanide blood and lactate concentrations and reduction in mean arterial pressure from baseline were similar. In the saline solution group, 2 of 11 animals survived compared with 10 of 11 in the hydroxocobalamin and Cobinamide groups ( P Conclusion Both hydroxocobalamin and Cobinamide rescued severely cyanide-poisoned swine from apnea in the absence of assisted ventilation. The dose of Cobinamide was one fifth that of hydroxocobalamin.

Sari B. Mahon - One of the best experts on this subject based on the ideXlab platform.

  • Intramuscular Cobinamide as an antidote to methyl mercaptan poisoning.
    Inhalation toxicology, 2020
    Co-Authors: Tara B. Hendry-hofer, Adriano Chan, Alison M. Mcgrath, Kirsten Soules, David Mukai, Joseph K. Maddry, Carl W. White, Jangwoen Lee, Sari B. Mahon
    Abstract:

    BACKGROUND Methyl mercaptan occurs naturally in the environment and is found in a variety of occupational settings, including the oil, paper, plastics, and pesticides industries. It is a toxic gas and deaths from methyl mercaptan exposure have occurred. The Department of Homeland Security considers it a high threat chemical agent that could be used by terrorists. Unfortunately, no specific treatment exists for methyl mercaptan poisoning. METHODS We conducted a randomized trial in 12 swine comparing no treatment to intramuscular injection of the vitamin B12 analog Cobinamide (2.0 mL, 12.5 mg/kg) following acute inhalation of methyl mercaptan gas. Physiological and laboratory parameters were similar in the control and Cobinamide-treated groups at baseline and at the time of treatment. RESULTS All six Cobinamide-treated animals survived, whereas only one of six control animals lived (17% survival) (p = 0.0043). The Cobinamide-treated animals returned to a normal breathing pattern by 3.8 ± 1.1 min after treatment (mean ± SD), while all but one animal in the control group had intermittent gasping, never regaining a normal breathing pattern. Blood pressure and arterial oxygen saturation returned to baseline values within 15 minutes of Cobinamide-treatment. Plasma lactate concentration increased progressively until death (10.93 ± 6.02 mmol [mean ± SD]) in control animals, and decreased toward baseline (3.79 ± 2.93 mmol [mean ± SD]) by the end of the experiment in Cobinamide-treated animals. CONCLUSION We conclude that intramuscular administration of Cobinamide improves survival and clinical outcomes in a large animal model of acute, high dose methyl mercaptan poisoning.

  • Intramuscular Aminotetrazole Cobinamide as a Treatment for Inhaled Hydrogen Sulfide Poisoning in a Large Swine Model
    Annals of the New York Academy of Sciences, 2020
    Co-Authors: Tara B. Hendry-hofer, Sari B. Mahon, Matthew Brenner, Alison M. Mcgrath, David Mukai, Joseph K. Maddry, Gerry R Boss, Vikhyat S. Bebarta
    Abstract:

    Hydrogen sulfide (H2 S), a high-threat chemical agent, occurs naturally in a variety of settings. Despite multiple incidents of exposures and deaths, no FDA-approved antidote exists. A rapid-acting, easy to administer antidote is needed. We conducted a randomized control trial in swine comparing intramuscular administration of aminotetrazole Cobinamide (2.9 mL, 18 mg/kg) to no treatment following inhalation of H2 S gas. We found that aminotetrazole Cobinamide administered 2 min after the onset of respiratory depression-defined as a tidal volume of less than 3 mL/kg for 2 consecutive minutes-yielded 100% survival, while all control animals died. Respiratory depression resolved in the treatment group within 3.6 ± 1.5 min (mean ± SD) of Cobinamide administration, whereas control animals had intermittent gasping until death. Blood pressure and arterial oxygen saturation (SO2 ) returned to baseline values within 5 and 10 min, respectively, of Cobinamide treatment, and plasma lactate concentration decreased to less than 50% of the highest value by the end of the experiment. In control animals, plasma lactate rose continuously until death. We conclude that intramuscular aminotetrazole Cobinamide is effective in a large animal, inhalational model of acute, severe H2 S poisoning.

  • efficacy of intravenous Cobinamide versus hydroxocobalamin or saline for treatment of severe hydrogen sulfide toxicity in a swine sus scrofa model
    Academic Emergency Medicine, 2017
    Co-Authors: Vikhyat S. Bebarta, Sari B. Mahon, Matthew Brenner, Joseph K. Maddry, Susan M Boudreau, Maria G Castaneda, Normalynn Garrett, Gerry R Boss
    Abstract:

    Background Hydrogen sulfide (H2S) is a potentially deadly gas that naturally occurs in petroleum and natural gas. The Occupational Health and Safety Administration cites H2S as a leading cause of workplace gas inhalation deaths. Mass casualties of H2S toxicity may be caused by exposure from industrial accidents or release from oil field sites. H2S is also an attractive terrorism tool because of its high toxicity and ease with which it can be produced. Several potential antidotes have been proposed for hydrogen sulfide poisoning but none have been completely successful. Objective To compare treatment response assessed by the time to spontaneous ventilation among groups of swine with acute H2S induced apnea treated with intravenous (IV) Cobinamide (4mg/kg in 0.8 ml of 225mM solution), IV hydroxocobalamin (4mg/kg in 5 ml saline), or saline alone. Methods Twenty-four swine (45-55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. After stabilization, anesthesia was adjusted such that animals would spontaneous ventilate with an FIO2 of 0.21. Sodium hydrosulfide (NaHS; concentration of 8 mg/ml) was begun at 1 mg/kg/min until apnea was confirmed for 20 seconds by capnography. This infusion rate was sustained for 1.5 minutes post apnea, and then decreased to a maintenance rate for the remainder of the study to replicate sustained clinical exposure. Animals were randomly assigned to receive Cobinamide (4 mg/kg), hydroxocobalamin (4 mg/kg) or saline and monitored for 60 minutes beginning one-minute post apnea. G* power analysis using the Z test determined that equal group sizes of 8 animals were needed to achieve a power of 80% in detecting a 50% difference in return to spontaneous ventilations at α=0.05. Results There were no significant differences in baseline variables. Moreover, there were no significant differences in the mg/kg dose of NaHS (5.6 mg/kg; p=0.45) required to produce apnea. Whereas all of the Cobinamide treated animals survived (8/8), none of the control (0/8) or hydroxocobalamin (0/8) treated animals survived. Mean time to spontaneous ventilation in the Cobinamide treated animals was 3.2(±1.1) minutes. Conclusions Cobinamide successfully rescued the severely NaHS-poisoned swine from apnea in the absence of assisted ventilation. This article is protected by copyright. All rights reserved.

  • The Vitamin B_12 Analog Cobinamide Is an Effective Antidote for Oral Cyanide Poisoning
    Journal of Medical Toxicology, 2016
    Co-Authors: Jangwoen Lee, Adriano Chan, Sari B. Mahon, David Mukai, Vikhyat S. Bebarta, Gerry R Boss, Tanya Burney, Behdod S Katebian, David Yoon, Matthew Brenner
    Abstract:

    Introduction Cyanide is a major chemical threat, and cyanide ingestion carries a higher risk for a supra-lethal dose exposure compared to inhalation but provides an opportunity for effective treatment due to a longer treatment window and a gastrointestinal cyanide reservoir that could be neutralized prior to systemic absorption. We hypothesized that orally administered Cobinamide may function as a high-binding affinity scavenger and that gastric alkalinization would reduce cyanide absorption and concurrently increase Cobinamide binding, further enhancing antidote effectiveness. Methods Thirty New Zealand white rabbits were divided into five groups and were given a lethal dose of oral cyanide poisoning (50 mg). The survival time of animals was monitored with oral cyanide alone, oral cyanide with gastric alkalinization with oral sodium bicarbonate buffer (500 mg), and in combination with either aquohydroxoCobinamide or dinitroCobinamide (250 mM). Red blood cell cyanide concentration, plasma Cobinamide, and thiocyanate concentrations were measured from blood samples. Results In cyanide ingested animals, oral sodium bicarbonate alone significantly prolonged survival time to 20.3 ± 8.6 min compared to 10.5 ± 4.3 min in saline-treated controls, but did not lead to overall survival. AquohydroxoCobinamide and dinitroCobinamide increased survival time to 64 ± 41 ( p  

  • the vitamin b12 analog Cobinamide is an effective antidote for oral cyanide poisoning
    Journal of Medical Toxicology, 2016
    Co-Authors: Jangwoen Lee, Adriano Chan, Sari B. Mahon, David Mukai, Vikhyat S. Bebarta, Gerry R Boss, Tanya Burney, Behdod S Katebian, David Yoon, Matthew Brenner
    Abstract:

    Introduction Cyanide is a major chemical threat, and cyanide ingestion carries a higher risk for a supra-lethal dose exposure compared to inhalation but provides an opportunity for effective treatment due to a longer treatment window and a gastrointestinal cyanide reservoir that could be neutralized prior to systemic absorption. We hypothesized that orally administered Cobinamide may function as a high-binding affinity scavenger and that gastric alkalinization would reduce cyanide absorption and concurrently increase Cobinamide binding, further enhancing antidote effectiveness.

Matthew Brenner - One of the best experts on this subject based on the ideXlab platform.

  • Intramuscular Aminotetrazole Cobinamide as a Treatment for Inhaled Hydrogen Sulfide Poisoning in a Large Swine Model
    Annals of the New York Academy of Sciences, 2020
    Co-Authors: Tara B. Hendry-hofer, Sari B. Mahon, Matthew Brenner, Alison M. Mcgrath, David Mukai, Joseph K. Maddry, Gerry R Boss, Vikhyat S. Bebarta
    Abstract:

    Hydrogen sulfide (H2 S), a high-threat chemical agent, occurs naturally in a variety of settings. Despite multiple incidents of exposures and deaths, no FDA-approved antidote exists. A rapid-acting, easy to administer antidote is needed. We conducted a randomized control trial in swine comparing intramuscular administration of aminotetrazole Cobinamide (2.9 mL, 18 mg/kg) to no treatment following inhalation of H2 S gas. We found that aminotetrazole Cobinamide administered 2 min after the onset of respiratory depression-defined as a tidal volume of less than 3 mL/kg for 2 consecutive minutes-yielded 100% survival, while all control animals died. Respiratory depression resolved in the treatment group within 3.6 ± 1.5 min (mean ± SD) of Cobinamide administration, whereas control animals had intermittent gasping until death. Blood pressure and arterial oxygen saturation (SO2 ) returned to baseline values within 5 and 10 min, respectively, of Cobinamide treatment, and plasma lactate concentration decreased to less than 50% of the highest value by the end of the experiment. In control animals, plasma lactate rose continuously until death. We conclude that intramuscular aminotetrazole Cobinamide is effective in a large animal, inhalational model of acute, severe H2 S poisoning.

  • efficacy of intravenous Cobinamide versus hydroxocobalamin or saline for treatment of severe hydrogen sulfide toxicity in a swine sus scrofa model
    Academic Emergency Medicine, 2017
    Co-Authors: Vikhyat S. Bebarta, Sari B. Mahon, Matthew Brenner, Joseph K. Maddry, Susan M Boudreau, Maria G Castaneda, Normalynn Garrett, Gerry R Boss
    Abstract:

    Background Hydrogen sulfide (H2S) is a potentially deadly gas that naturally occurs in petroleum and natural gas. The Occupational Health and Safety Administration cites H2S as a leading cause of workplace gas inhalation deaths. Mass casualties of H2S toxicity may be caused by exposure from industrial accidents or release from oil field sites. H2S is also an attractive terrorism tool because of its high toxicity and ease with which it can be produced. Several potential antidotes have been proposed for hydrogen sulfide poisoning but none have been completely successful. Objective To compare treatment response assessed by the time to spontaneous ventilation among groups of swine with acute H2S induced apnea treated with intravenous (IV) Cobinamide (4mg/kg in 0.8 ml of 225mM solution), IV hydroxocobalamin (4mg/kg in 5 ml saline), or saline alone. Methods Twenty-four swine (45-55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. After stabilization, anesthesia was adjusted such that animals would spontaneous ventilate with an FIO2 of 0.21. Sodium hydrosulfide (NaHS; concentration of 8 mg/ml) was begun at 1 mg/kg/min until apnea was confirmed for 20 seconds by capnography. This infusion rate was sustained for 1.5 minutes post apnea, and then decreased to a maintenance rate for the remainder of the study to replicate sustained clinical exposure. Animals were randomly assigned to receive Cobinamide (4 mg/kg), hydroxocobalamin (4 mg/kg) or saline and monitored for 60 minutes beginning one-minute post apnea. G* power analysis using the Z test determined that equal group sizes of 8 animals were needed to achieve a power of 80% in detecting a 50% difference in return to spontaneous ventilations at α=0.05. Results There were no significant differences in baseline variables. Moreover, there were no significant differences in the mg/kg dose of NaHS (5.6 mg/kg; p=0.45) required to produce apnea. Whereas all of the Cobinamide treated animals survived (8/8), none of the control (0/8) or hydroxocobalamin (0/8) treated animals survived. Mean time to spontaneous ventilation in the Cobinamide treated animals was 3.2(±1.1) minutes. Conclusions Cobinamide successfully rescued the severely NaHS-poisoned swine from apnea in the absence of assisted ventilation. This article is protected by copyright. All rights reserved.

  • The Vitamin B_12 Analog Cobinamide Is an Effective Antidote for Oral Cyanide Poisoning
    Journal of Medical Toxicology, 2016
    Co-Authors: Jangwoen Lee, Adriano Chan, Sari B. Mahon, David Mukai, Vikhyat S. Bebarta, Gerry R Boss, Tanya Burney, Behdod S Katebian, David Yoon, Matthew Brenner
    Abstract:

    Introduction Cyanide is a major chemical threat, and cyanide ingestion carries a higher risk for a supra-lethal dose exposure compared to inhalation but provides an opportunity for effective treatment due to a longer treatment window and a gastrointestinal cyanide reservoir that could be neutralized prior to systemic absorption. We hypothesized that orally administered Cobinamide may function as a high-binding affinity scavenger and that gastric alkalinization would reduce cyanide absorption and concurrently increase Cobinamide binding, further enhancing antidote effectiveness. Methods Thirty New Zealand white rabbits were divided into five groups and were given a lethal dose of oral cyanide poisoning (50 mg). The survival time of animals was monitored with oral cyanide alone, oral cyanide with gastric alkalinization with oral sodium bicarbonate buffer (500 mg), and in combination with either aquohydroxoCobinamide or dinitroCobinamide (250 mM). Red blood cell cyanide concentration, plasma Cobinamide, and thiocyanate concentrations were measured from blood samples. Results In cyanide ingested animals, oral sodium bicarbonate alone significantly prolonged survival time to 20.3 ± 8.6 min compared to 10.5 ± 4.3 min in saline-treated controls, but did not lead to overall survival. AquohydroxoCobinamide and dinitroCobinamide increased survival time to 64 ± 41 ( p  

  • the vitamin b12 analog Cobinamide is an effective antidote for oral cyanide poisoning
    Journal of Medical Toxicology, 2016
    Co-Authors: Jangwoen Lee, Adriano Chan, Sari B. Mahon, David Mukai, Vikhyat S. Bebarta, Gerry R Boss, Tanya Burney, Behdod S Katebian, David Yoon, Matthew Brenner
    Abstract:

    Introduction Cyanide is a major chemical threat, and cyanide ingestion carries a higher risk for a supra-lethal dose exposure compared to inhalation but provides an opportunity for effective treatment due to a longer treatment window and a gastrointestinal cyanide reservoir that could be neutralized prior to systemic absorption. We hypothesized that orally administered Cobinamide may function as a high-binding affinity scavenger and that gastric alkalinization would reduce cyanide absorption and concurrently increase Cobinamide binding, further enhancing antidote effectiveness.

  • Hydrogen Sulfide—Mechanisms of Toxicity and Development of an Antidote
    Scientific Reports, 2016
    Co-Authors: Jingjing Jiang, Sameh Ali, Kristofer J. Haushalter, Wai Ling Mac Rina Lam, Megan Glasheen, Arindam Saha, Adriano Chan, Matthew Brenner, James Parker, Sari B. Mahon
    Abstract:

    Hydrogen sulfide is a highly toxic gas—second only to carbon monoxide as a cause of inhalational deaths. Its mechanism of toxicity is only partially known and no specific therapy exists for sulfide poisoning. We show in several cell types, including human inducible pluripotent stem cell (hiPSC)-derived neurons, that sulfide inhibited complex IV of the mitochondrial respiratory chain and induced apoptosis. Sulfide increased hydroxyl radical production in isolated mouse heart mitochondria and F_2-isoprostanes in brains and hearts of mice. The vitamin B_12 analog Cobinamide reversed the cellular toxicity of sulfide and rescued Drosophila melanogaster and mice from lethal exposures of hydrogen sulfide gas. Cobinamide worked through two distinct mechanisms: direct reversal of complex IV inhibition and neutralization of sulfide-generated reactive oxygen species. We conclude that sulfide produces a high degree of oxidative stress in cells and tissues and that Cobinamide has promise as a first specific treatment for sulfide poisoning.

Vikhyat S. Bebarta - One of the best experts on this subject based on the ideXlab platform.

  • Intramuscular Aminotetrazole Cobinamide as a Treatment for Inhaled Hydrogen Sulfide Poisoning in a Large Swine Model
    Annals of the New York Academy of Sciences, 2020
    Co-Authors: Tara B. Hendry-hofer, Sari B. Mahon, Matthew Brenner, Alison M. Mcgrath, David Mukai, Joseph K. Maddry, Gerry R Boss, Vikhyat S. Bebarta
    Abstract:

    Hydrogen sulfide (H2 S), a high-threat chemical agent, occurs naturally in a variety of settings. Despite multiple incidents of exposures and deaths, no FDA-approved antidote exists. A rapid-acting, easy to administer antidote is needed. We conducted a randomized control trial in swine comparing intramuscular administration of aminotetrazole Cobinamide (2.9 mL, 18 mg/kg) to no treatment following inhalation of H2 S gas. We found that aminotetrazole Cobinamide administered 2 min after the onset of respiratory depression-defined as a tidal volume of less than 3 mL/kg for 2 consecutive minutes-yielded 100% survival, while all control animals died. Respiratory depression resolved in the treatment group within 3.6 ± 1.5 min (mean ± SD) of Cobinamide administration, whereas control animals had intermittent gasping until death. Blood pressure and arterial oxygen saturation (SO2 ) returned to baseline values within 5 and 10 min, respectively, of Cobinamide treatment, and plasma lactate concentration decreased to less than 50% of the highest value by the end of the experiment. In control animals, plasma lactate rose continuously until death. We conclude that intramuscular aminotetrazole Cobinamide is effective in a large animal, inhalational model of acute, severe H2 S poisoning.

  • efficacy of intravenous Cobinamide versus hydroxocobalamin or saline for treatment of severe hydrogen sulfide toxicity in a swine sus scrofa model
    Academic Emergency Medicine, 2017
    Co-Authors: Vikhyat S. Bebarta, Sari B. Mahon, Matthew Brenner, Joseph K. Maddry, Susan M Boudreau, Maria G Castaneda, Normalynn Garrett, Gerry R Boss
    Abstract:

    Background Hydrogen sulfide (H2S) is a potentially deadly gas that naturally occurs in petroleum and natural gas. The Occupational Health and Safety Administration cites H2S as a leading cause of workplace gas inhalation deaths. Mass casualties of H2S toxicity may be caused by exposure from industrial accidents or release from oil field sites. H2S is also an attractive terrorism tool because of its high toxicity and ease with which it can be produced. Several potential antidotes have been proposed for hydrogen sulfide poisoning but none have been completely successful. Objective To compare treatment response assessed by the time to spontaneous ventilation among groups of swine with acute H2S induced apnea treated with intravenous (IV) Cobinamide (4mg/kg in 0.8 ml of 225mM solution), IV hydroxocobalamin (4mg/kg in 5 ml saline), or saline alone. Methods Twenty-four swine (45-55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. After stabilization, anesthesia was adjusted such that animals would spontaneous ventilate with an FIO2 of 0.21. Sodium hydrosulfide (NaHS; concentration of 8 mg/ml) was begun at 1 mg/kg/min until apnea was confirmed for 20 seconds by capnography. This infusion rate was sustained for 1.5 minutes post apnea, and then decreased to a maintenance rate for the remainder of the study to replicate sustained clinical exposure. Animals were randomly assigned to receive Cobinamide (4 mg/kg), hydroxocobalamin (4 mg/kg) or saline and monitored for 60 minutes beginning one-minute post apnea. G* power analysis using the Z test determined that equal group sizes of 8 animals were needed to achieve a power of 80% in detecting a 50% difference in return to spontaneous ventilations at α=0.05. Results There were no significant differences in baseline variables. Moreover, there were no significant differences in the mg/kg dose of NaHS (5.6 mg/kg; p=0.45) required to produce apnea. Whereas all of the Cobinamide treated animals survived (8/8), none of the control (0/8) or hydroxocobalamin (0/8) treated animals survived. Mean time to spontaneous ventilation in the Cobinamide treated animals was 3.2(±1.1) minutes. Conclusions Cobinamide successfully rescued the severely NaHS-poisoned swine from apnea in the absence of assisted ventilation. This article is protected by copyright. All rights reserved.

  • The Vitamin B_12 Analog Cobinamide Is an Effective Antidote for Oral Cyanide Poisoning
    Journal of Medical Toxicology, 2016
    Co-Authors: Jangwoen Lee, Adriano Chan, Sari B. Mahon, David Mukai, Vikhyat S. Bebarta, Gerry R Boss, Tanya Burney, Behdod S Katebian, David Yoon, Matthew Brenner
    Abstract:

    Introduction Cyanide is a major chemical threat, and cyanide ingestion carries a higher risk for a supra-lethal dose exposure compared to inhalation but provides an opportunity for effective treatment due to a longer treatment window and a gastrointestinal cyanide reservoir that could be neutralized prior to systemic absorption. We hypothesized that orally administered Cobinamide may function as a high-binding affinity scavenger and that gastric alkalinization would reduce cyanide absorption and concurrently increase Cobinamide binding, further enhancing antidote effectiveness. Methods Thirty New Zealand white rabbits were divided into five groups and were given a lethal dose of oral cyanide poisoning (50 mg). The survival time of animals was monitored with oral cyanide alone, oral cyanide with gastric alkalinization with oral sodium bicarbonate buffer (500 mg), and in combination with either aquohydroxoCobinamide or dinitroCobinamide (250 mM). Red blood cell cyanide concentration, plasma Cobinamide, and thiocyanate concentrations were measured from blood samples. Results In cyanide ingested animals, oral sodium bicarbonate alone significantly prolonged survival time to 20.3 ± 8.6 min compared to 10.5 ± 4.3 min in saline-treated controls, but did not lead to overall survival. AquohydroxoCobinamide and dinitroCobinamide increased survival time to 64 ± 41 ( p  

  • the vitamin b12 analog Cobinamide is an effective antidote for oral cyanide poisoning
    Journal of Medical Toxicology, 2016
    Co-Authors: Jangwoen Lee, Adriano Chan, Sari B. Mahon, David Mukai, Vikhyat S. Bebarta, Gerry R Boss, Tanya Burney, Behdod S Katebian, David Yoon, Matthew Brenner
    Abstract:

    Introduction Cyanide is a major chemical threat, and cyanide ingestion carries a higher risk for a supra-lethal dose exposure compared to inhalation but provides an opportunity for effective treatment due to a longer treatment window and a gastrointestinal cyanide reservoir that could be neutralized prior to systemic absorption. We hypothesized that orally administered Cobinamide may function as a high-binding affinity scavenger and that gastric alkalinization would reduce cyanide absorption and concurrently increase Cobinamide binding, further enhancing antidote effectiveness.

  • intravenous Cobinamide versus hydroxocobalamin for acute treatment of severe cyanide poisoning in a swine sus scrofa model
    Annals of Emergency Medicine, 2014
    Co-Authors: Vikhyat S. Bebarta, Susan M Boudreau, Maria G Castaneda, David A Tanen, Lee A Zarzabal, Toni E Vargas, Gerry R Boss
    Abstract:

    Study objective Hydroxocobalamin is a Food and Drug Administration–approved antidote for cyanide poisoning. Cobinamide is a potential antidote that contains 2 cyanide-binding sites. To our knowledge, no study has directly compared hydroxocobalamin with Cobinamide in a severe, cyanide-toxic large-animal model. Our objective is to compare the time to return of spontaneous breathing in swine with acute cyanide-induced apnea treated with intravenous hydroxocobalamin, intravenous Cobinamide, or saline solution (control). Methods Thirty-three swine (45 to 55 kg) were intubated, anesthetized, and instrumented (continuous mean arterial pressure and cardiac output monitoring). Anesthesia was adjusted to allow spontaneous breathing with FiO 2 of 21% during the experiment. Cyanide was continuously infused intravenously until apnea occurred and lasted for 1 minute (time zero). Animals were then randomly assigned to receive intravenous hydroxocobalamin (65 mg/kg), Cobinamide (12.5 mg/kg), or saline solution and monitored for 60 minutes. A sample size of 11 animals per group was selected according to obtaining a power of 80%, an α of .05, and an SD of 0.17 in mean time to detect a 20% difference in time to spontaneous breathing. We assessed differences in time to death among groups, using Kaplan-Meier estimation methods, and compared serum lactate, blood pH, cardiac output, mean arterial pressure, respiratory rate, and minute ventilation time curves with repeated-measures ANOVA. Results Baseline weights and vital signs were similar among groups. The time to apnea and cyanide dose required to achieve apnea were similar. At time zero, mean cyanide blood and lactate concentrations and reduction in mean arterial pressure from baseline were similar. In the saline solution group, 2 of 11 animals survived compared with 10 of 11 in the hydroxocobalamin and Cobinamide groups ( P Conclusion Both hydroxocobalamin and Cobinamide rescued severely cyanide-poisoned swine from apnea in the absence of assisted ventilation. The dose of Cobinamide was one fifth that of hydroxocobalamin.

Vijay S Sharma - One of the best experts on this subject based on the ideXlab platform.

  • Intramuscular Cobinamide sulfite in a rabbit model of sublethal cyanide toxicity.
    Annals of emergency medicine, 2010
    Co-Authors: Matthew Brenner, Sari B. Mahon, David Mukai, Jangwoen Lee, Jae Gwan Kim, K. Kreuter, William Blackledge, Steven E. Patterson, Othman Mohammad, Vijay S Sharma
    Abstract:

    Study objective Exposure to cyanide in fires and industrial exposures and intentional cyanide poisoning by terrorists leading to mass casualties is an ongoing threat. Current treatments for cyanide poisoning must be administered intravenously, and no rapid treatment methods are available for mass casualty cyanide exposures. Cobinamide is a cobalamin (vitamin B 12 ) analog with an extraordinarily high affinity for cyanide that is more water-soluble than cobalamin. We investigate the use of intramuscular Cobinamide sulfite to reverse cyanide toxicity–induced physiologic changes in a sublethal cyanide exposure animal model and determine the ability of an intramuscular Cobinamide sulfite injection to rapidly reverse the physiologic effects of cyanide toxicity. Methods New Zealand white rabbits were given 10 mg sodium cyanide intravenously over 60 minutes. Quantitative diffuse optical spectroscopy and continuous-wave near-infrared spectroscopy monitoring of tissue oxyhemoglobin and deoxyhemoglobin concentrations were performed concurrently with blood cyanide level measurements and Cobinamide levels. Immediately after completion of the cyanide infusion, the rabbits were injected intramuscularly with Cobinamide sulfite (n=6) or inactive vehicle (controls, n=5). Results Intramuscular administration led to rapid mobilization of Cobinamide and was extremely effective at reversing the physiologic effects of cyanide on oxyhemoglobin and within deoxyhemoglobin extraction. Recovery time to 63% of their baseline values in the central nervous system occurred within a mean of 1,032 minutes in the control group and 9 minutes in the Cobinamide group, with a difference of 1,023 minutes (95% confidence interval 116 to 1,874 minutes). In muscle tissue, recovery times were 76 and 24 minutes, with a difference of 52 minutes (95% confidence interval 7 to 98 minutes). RBC cyanide levels returned toward normal significantly faster in Cobinamide sulfite–treated animals than in control animals. Conclusion Intramuscular Cobinamide sulfite rapidly and effectively reverses the physiologic effects of cyanide poisoning, suggesting that a compact cyanide antidote kit can be developed for mass casualty cyanide exposures.

  • Comparison of Cobinamide to hydroxocobalamin in reversing cyanide physiologic effects in rabbits using diffuse optical spectroscopy monitoring
    Journal of biomedical optics, 2010
    Co-Authors: Matthew Brenner, Sari B. Mahon, David Mukai, Jangwoen Lee, Jae Gwan Kim, K. Kreuter, Othman Mohammad, Seth Goodman, Rebecca Ahdout, Vijay S Sharma
    Abstract:

    Our purpose is to compare Cobinamide to hydroxocobal- amin in reversing cyanide CN-induced physiologic effects in an ani- mal model using diffuse optical spectroscopy DOS. Cyanide poison- ing is a major threat worldwide. Cobinamide is a novel molecule that can bind two molecules of cyanide, has a much higher binding affin- ity than hydroxocobalamin, and is more water soluble. We investi- gated the ability of equimolar doses of Cobinamide and hydroxoco- balamin to reverse the effects of cyanide exposure in an animal model monitored continuously by DOS. Cyanide toxicity was induced in 16 New Zealand white rabbits by intravenous infusion. Animals were divided into three groups: controls n=5 received saline following cyanide, hydroxocobalamin N=6 following cyanide, and cobina- mide N=5 following cyanide. Cobinamide caused significantly faster and more complete recovery of oxy- and deoxyhemoglobin concentrations in cyanide-exposed animals than hydroxocobalamin- or saline-treated animals, with a recovery time constant of 13.8±7.1 min compared to 75.4±25.1 and 76.4±42.7 min, for hydroxocobalamin- and saline-treated animals, respectively p0.0001. This study indicates that Cobinamide more rapidly and completely reverses the physiologic effects of cyanide than equimolar doses of cobalamin at the dose used in this study, and CN effects and response can be followed noninvasively using DOS. © 2010 Society of

  • The cobalamin precursor Cobinamide detoxifies nitroprusside-generated cyanide.
    Experimental biology and medicine (Maywood N.J.), 2007
    Co-Authors: Kate E Broderick, Adriano Chan, Vijay S Sharma, Renate B Pilz, Maheswari Balasubramanian, Prasanth Potluri, F. Jake Feala, Darrell D. Belke, Andrew D. Mcculloch, Timothy D. Bigby
    Abstract:

    Sodium nitroprusside is used to treat hypertensive emergencies and acute heart failure. It acts by releasing nitric oxide (NO), a highly potent vasodilator, but unfortunately, for each NO molecule released, five cyanide ions are released. Thus, nitroprusside therapy is limited by cyanide toxicity. Therefore, a cyanide scavenger could be beneficial when administering nitroprusside. Hydroxocobalamin, which has a relatively high binding affinity for cyanide, has been shown to reduce cyanide levels in nitroprusside-treated patients. Cobinamide, the penultimate precursor in hydroxocobalamin biosynthesis, has a much greater affinity for cyanide than cobalamin, and binds two cyanide ions. We now show that Cobinamide is highly effective in neutralizing cyanide ions released by nitroprusside in cultured mammalian cells, Drosophila melanogaster, and mice. Cobinamide also binds NO, but at molar concentrations 2.5-5 times that of nitroprusside, it did not decrease NO concentrations or the physiological effectiveness of nitroprusside. We conclude that Cobinamide could be a valuable adjunct to nitroprusside therapy.

  • cyanide detoxification by the cobalamin precursor Cobinamide
    Experimental Biology and Medicine, 2006
    Co-Authors: Kate E Broderick, Shunhui Zhuang, Vijay S Sharma, Renate B Pilz, Prasanth Potluri, Immo E Scheffler, Gerry R Boss
    Abstract:

    Cyanide is a highly toxic agent that inhibits mitochondrial cytochrome-c oxidase, thereby depleting cellular ATP. It contributes to smoke inhalation deaths in fires and could be used as a weapon of mass destruction. Cobalamin (vitamin B12) binds cyanide with a relatively high affinity and is used in Europe to treat smoke inhalation victims. Cobinamide, the penultimate compound in cobalamin biosynthesis, binds cyanide with about 10(10) greater affinity than cobalamin, and we found it was several-fold more effective than cobalamin in (i) reversing cyanide inhibition of oxidative phosphorylation in mammalian cells; (ii) rescuing mammalian cells and Drosophila melanogaster from cyanide toxicity; and (iii) reducing cyanide inhibition of Drosophila Malpighian tubule secretion. Cobinamide could be delivered by oral ingestion, inhalation, or injection to Drosophila, and it was as effective when administered up to 5 mins post-cyanide exposure as when given pre-exposure. We conclude that Cobinamide is an effective cyanide detoxifying agent that has potential use as a cyanide antidote, both in smoke inhalation victims and in persons exposed to cyanide used as a weapon of mass destruction.

  • nitric oxide scavenging by the cobalamin precursor Cobinamide
    Journal of Biological Chemistry, 2005
    Co-Authors: Kate E Broderick, Shunhui Zhuang, Veena Singh, Amanpreet Kambo, Jeffrey C Chen, Vijay S Sharma, Renate B Pilz, Gerry R Boss
    Abstract:

    Abstract Nitric oxide (NO) is an important signaling molecule, and a number of NO synthesis inhibitors and scavengers have been developed to allow study of NO functions and to reduce excess NO levels in disease states. We showed previously that Cobinamide, a cobalamin (vitamin B12) precursor, binds NO with high affinity, and we now evaluated the potential of Cobinamide as a NO scavenger in biologic systems. We found that Cobinamide reversed NO-stimulated fluid secretion in Drosophila Malpighian tubules, both when applied in the form of a NO donor and when produced intracellularly by nitricoxide synthase. Moreover, feeding flies Cobinamide markedly attenuated subsequent NO-induced increases in tubular fluid secretion. Cobinamide was taken up efficiently by cultured rodent cells and prevented NO-induced phosphorylation of the vasodilator-stimulated phosphoprotein VASP both when NO was provided to the cells and when NO was generated intracellularly. Cobinamide appeared to act via scavenging NO because it reduced nitrite and nitrate concentrations in both the fly and mammalian cell systems, and it did not interfere with cGMP-induced phosphorylation of VASP. In rodent and human cells, Cobinamide exhibited toxicity at concentrations ≥50 μm with toxicity completely prevented by providing equimolar amounts of cobalamin. Combining cobalamin with Cobinamide had no effect on the ability of Cobinamide to scavenge NO. Cobinamide did not inhibit the in vitro activity of either of the two mammalian cobalamin-dependent enzymes, methionine synthase or methylmalonyl-coenzyme A mutase; however, it did inhibit the in vivo activities of the enzymes in the absence, but not presence, of cobalamin, suggesting that Cobinamide toxicity was secondary to interference with cobalamin metabolism. As part of these studies, we developed a facile method for producing and purifying Cobinamide. We conclude that Cobinamide is an effective intra- and extracellular NO scavenger whose modest toxicity can be eliminated by cobalamin.